De novo , structure-based rational design of new metal centers into proteins of known structure is a novel approach for the study of fundamental principles of molecular recognition. The goal of this work is twofold: mimicry of natural sites to explore relationships between structure and function in ways that are not possible by the study of the sites in their natural environment; and the construction of sites not previously encountered in Nature in order to create proteins with new novel properties. We have undertaken the design of mimics of the well-known Type I Blue Copper sites into E. coli thioredoxin, a protein that normally does not possess any metal centers.